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The absence of IRG1 exacerbates bone loss in a mouse model of ovariectomy-induced osteoporosis by increasing osteoclastogenesis through the potentiation of NLRP3 inflammasome activation.

作者信息

Wang Fang, Liu Yanqiao, Zhao Yanqin, Zheng Hongyin, Zhang Lei

机构信息

Department of Endocrinology, Sichuan Provincial People's Hospital, Southwest Medical University, Luzhou, Sichuan 646099, China.

Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.

出版信息

Int Immunopharmacol. 2025 Feb 20;148:114099. doi: 10.1016/j.intimp.2025.114099. Epub 2025 Jan 26.

DOI:10.1016/j.intimp.2025.114099
PMID:39870006
Abstract

The immune-responsive gene 1 (IRG1) protein plays a role in various pathological processes by connecting cellular metabolism to a range of cellular activities through the production of itaconate. Recent studies have highlighted the significance of IRG1 and itaconate in bone metabolism and homeostasis. However, the precise role of IRG1 in osteoporosis remains inadequately documented. This study aimed to determine the role of IRG1 in osteoporosis through the utilization of IRG1 knockout (KO) mice and a model of ovariectomy (OVX)-induced osteoporosis. The expression of IRG1 was found to be higher in the bone tissues of postmenopausal osteoporotic mice induced by OVX in comparison to sham control mice. When compared to wild type (WT) mice, OVX-induced bone loss was significantly worse in IRG1 KO mice, and this was accompanied by an increase in osteoclastogenesis and bone resorption. However, the loss of bone and the process of osteoclastogenesis and bone resorption were effectively reversed when the IRG1 KO mice were replenished with itaconate. The osteoclastogenesis induced by receptor activator of nuclear factor kappa-Β ligand (RANKL) in bone marrow-derived macrophages (BMMs) was found to be enhanced by IRG1 deficiency, which could be reversed through the replenishment of itaconate. Further investigation revealed that IRG1 deficiency potentiated the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The inhibition of NLRP3 inflammasome using a targeted inhibitor significantly ameliorated RANKL-induced osteoclastogenesis in IRG1 KO BMMs. Overall, this study highlights the significance of IRG1 in regulating osteoclastogenesis and proposes it as a potential target for osteoporosis treatment.

摘要

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